Sufentanil is a member of the series of potent fentanyl analogs. It has a high selectivity and affinity (approximately 10 times greater than fentanyl) for “mu” opiate receptors. When compared with fentanyl, sufentanil's pharmacokinetic profile shows a smaller volume of distribution, resulting in a terminal half-life intermediate between alfentanil and fentanyl. Additionally, sufentanil, like fentanyl, does not cause histamine release. The chemical name for sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienypethyl]-4-piperidinyl]-N-phenylpropanamide. In its citrate form, the chemical name is N-[4-(methoxymethyl)-1-[2-(2-thienypethyl]-4-piperidinyl]-N-phenylpropanamide, 2-hydroxy-1,2,3-propanetricarboxylate.
The classical approach for preparing sufentanil citrate involves forming the salt from sufentanil base with citric acid (using an approximate 1:1 ratio) in water with charging everything upfront. Unfortunately, this approach leads to the salt oiling out of solution and later crystallizing. This prior process also presents several other problems. First, considerable manual intervention is required to remove the aggregated product from the sidewalls of the reactor after the oiled-out product crystallizes. The uncontrolled crystallization causes the product to solidify into chunks that must be sieved or milled to obtain to a powder fine enough for pharmaceutical formulation. Milling of such a potent compound also is extremely hazardous and raises exposure issues. Furthermore, a polishing sterile filtration is not possible since the reaction does not go through a homogeneous phase. Single step reprocessing is also not possible (e.g., the material does not redissolve in the matrix). If the sufentanil citrate product fails specifications (e.g., assay, HPLC, particulate matter, etc.), the salt must be returned to the base form and the citrate crystallization process must be repeated from the beginning. A need therefore exists for an improved salt formation and isolation method to address the latter problems.